Burden of illness in progressive fibrosing interstitial lung disease

BACKGROUND: Progressive fibrosing interstitial lung disease (ILD) is a relatively new clinical concept describing a variety of ILDs characterized by progressive pulmonary fibrosis with associated lung function decline and worsening chest imaging. Little is known about health care resource utilization (HCRU) and costs associated with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF). This study analyzed the adjusted HCRU and cost burden among patients with incident non-IPF progressive fibrosing ILD vs matched patients with incident fibrosing ILD that had not yet progressed. METHODS: This was a retrospective study of insured US adults newly diagnosed with non-IPF fibrosing ILD from October 2016 to June 2019, conducted using administrative claims data from the Optum Research Database. Progressive disease was identified using claims-based proxies comprising health care utilization associated with management of progressive fibrosing ILD. Patients in the progressive population were 1:1 propensity score matched to not-yet-progressed patients on the basis of baseline demographic and clinical characteristics. All-cause HCRU and health care costs were presented as weighted per-patient-per-month (PPPM) measures to account for variable follow-up. Differences in study outcomes between matched cohorts were evaluated using Z-tests for continuous measures and Rao-Scott tests for binary measures. RESULTS: The postmatch cohorts comprised 11,025 patients with evidence of progression matched to 11,025 patients with not-yet-progressed fibrosing ILD. Mean (SD) weighted PPPM counts of follow-up health care encounters were significantly higher for the progressive vs not-yet-progressed cohort: ambulatory visits, 4.2 (3.6) vs 3.1 (3.3); emergency department visits, 0.3 (0.5) vs 0.1 (0.3); and inpatient (IP) stays, 0.1 (0.2) vs 0.0 (0.1) (P < 0.001 for all). Among patients with an IP stay, those with progressive disease had more inpatient days than those with not-yet-progressed disease (mean [SD] 1.6 [2.4] days vs 1.0 [1.3] days, P < 0.001). Mean weighted PPPM (SD) all-cause health care costs were also significantly higher for progressive vs not-yet-progressed patients, including total costs ($4,382 [$9,597] vs $2,243 [$4,162], P < 0.001), medical costs ($3,662 [$9,150] vs $1,627 [$3,524], P < 0.001), and pharmacy costs ($720 [$2,097] vs $616 [$2,070], P = 0.002). The difference in medical costs between cohorts was driven primarily by higher inpatient costs for progressive vs not-yet-progressed patients ($1,729 [$7,557] vs $523 [$2,118], P < 0.001). CONCLUSIONS: Progressive fibrosing ILD carries a substantial economic and health care burden. Among patients with incident non-IPF fibrosing ILD, all-cause HCRU and costs were significantly higher for those with a progressive phenotype than for matched patients whose disease had not yet progressed. The cost differential was driven primarily by hospitalizations, which were longer and more frequent for the progressive cohort.


METHODS:
This was a retrospective study of insured US adults newly diagnosed with non-IPF fibrosing ILD from October 2016 to June 2019, conducted using administrative claims data from the Optum Research Database. Progressive disease was identified using claims-based proxies comprising health care utilization associated with management of progressive fibrosing ILD. Patients in the progressive population were 1:1 propensity score matched to not-yet-progressed patients on the basis of baseline demographic and clinical characteristics. All-cause HCRU and health care costs were presented as weighted per-patient-per-month (PPPM) measures to account for variable follow-up. Differences in study outcomes between matched cohorts were evaluated using Z-tests for continuous measures and Rao-Scott tests for binary measures.

RESULTS:
The postmatch cohorts comprised 11,025 patients with evidence of progression matched to 11,025 patients with not-yet-progressed fibrosing ILD. Mean (SD) weighted PPPM counts of follow-up health care encounters were significantly higher for the progressive vs not-yet-progressed cohort: ambulatory visits, 4.2 (3.6) vs 3.1 (3.3); emergency department visits, 0.3 (0.5) vs 0.1 (0.3); and inpatient (IP) stays, 0.1 (0.2) vs 0.0 (0.1) (P < 0.001 for all). Among patients with an IP stay, those with progressive disease had more inpatient days than those with not-yet-progressed disease (mean [SD] 1.6 [2.4]  CONCLUSIONS: Progressive fibrosing ILD carries a substantial economic and health care burden. Among patients with incident non-IPF fibrosing ILD, all-cause HCRU and costs were significantly higher for those with a progressive phenotype than for matched patients whose disease had not yet progressed. The cost differential was driven primarily by hospitalizations, which were longer and more frequent for the progressive cohort.

Plain language summary
There are limited data on the burden of progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We found that health care use and costs for patients with a new non-IPF fibrosing ILD diagnosis were higher if they had progressive disease than if their disease had not yet progressed. Higher costs for progressive patients were due mostly to longer and more frequent hospital stays.

Implications for managed care pharmacy
Non-IPF progressive fibrosing ILD carries substantial health care and economic costs, which are driven primarily by hospitalizations. Awareness of this burden and implementation of disease management approaches that reduce hospitalization risk are critical to minimizing the impact of progressive fibrosing ILD on patients and health care systems.
Chronic fibrosing interstitial lung disease (ILD) with a progressive phenotype comprises a variety of interstitial lung diseases characterized by progressive fibrosis, with associated lung function decline and increasing chest imaging abnormalities. 1,2 The clinical course of these disorders follows a similar path independent of the underlying cause of disease, as the development of self-sustaining progressive fibrosis appears to be mediated by a shared underlying pathophysiology. 3 It is thought that approximately 1 in 4 patients with fibrosing ILD will develop a progressive phenotype. 4 These patients not only have persistent and worsening symptoms such as cough, dyspnea, and fatigue as well as impaired quality of life but also face early mortality, with median survival times as low as 3-5 years after diagnosis. [5][6][7][8] The prevalence of progressive fibrosing ILD has been difficult to determine because the disorders it comprises are numerous and diagnostically complex, but it was recently estimated to range from 0.89 per 10,000 to 2.36 per 10,000 for commercially insured patients and from 12.14 per 10,000 to 29.05 per 10,000 for Medicare beneficiaries in the United States. 9 Idiopathic pulmonary fibrosis (IPF) is the most common and well-defined progressive fibrosing ILD; accordingly, the health and economic burden of IPF has been documented. [10][11][12][13] However, little is known about health care resource utilization (HCRU) and costs associated with other forms of progressive fibrosing ILD. Administrative claims provide a rich source of real-world clinical and economic data, but the use of claims for analyzing progressive fibrotic ILD presents some challenges. There was no specific diagnosis code for this disease behavior until October 2020, as it is a relatively new clinical concept. Moreover, administrative claims do not include information about patient symptoms or results from chest imaging and pulmonary function tests, which are necessary to identify the hallmark features of the progressive phenotype. Recent descriptive claims studies have found that patients with progressive fibrotic ILD have higher HCRU and costs than those without progressive disease, but these analyses were not conducted on matched populations or adjusted for potential confounders, such as comorbidities. 14,15 In the present study, we estimated the adjusted HCRU and cost burden among patients with incident non-IPF progressive fibrosing ILD vs matched patients with incident fibrosing ILD that has not yet progressed.

STUDY DESIGN AND DATA SOURCE
This was a retrospective observational study conducted using administrative claims data from the Optum Research Disease progression was identified using claims-based proxies developed in consultation with clinical experts. 9 ILD = interstitial lung disease.

FIGURE 1
Study Period Schematic Index date: Date of earliest evidence of progression during identification period (progressive cohort) or assigned (not-yet-progressed cohort)

Follow-up period ≥ 3 months (variable)
Patients with not-yet-progressed fibrosing ILD were allowed to serve as controls for multiple patients in the progressive cohort and were also included in the progressive cohort if they subsequently developed evidence of disease progression. a Fibrosing ILD diagnosis codes were described in detail previously. 9 b International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis code J84.112. c Progression criteria include procedures, therapies, tests, and other health care utilization associated with management of progressive fibrosing ILD (described in detail previously 9 ). d Index dates for patients in the not-yet-progressed cohort were assigned so that the length of time from the fibrosing ILD diagnosis date to the index date was the same for the matched progressive and not-yet-progressed patients. ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis.

FIGURE 2
Patient Identification and Attrition Not-yet-progressed cohort Not-yet-progressed patients with ≥ 3 months of progression-free follow-up matched to progressive patients (index date is assigned d ) n = 11,025 Progressive cohort Progressive patients matched to not-yet-progressed patients with ≥ 3 months of progression-free follow-up (date of progression is index date) n = 11,025 Continuous enrollment for ≥ 3 months following index date (follow-up period) and during same continuous enrollment period as fibrosing ILD diagnosis date n = 11,031 (85.6%)

Prematch populations
Postmatch populations claims include drug name, National Drug Code, dosage form, drug strength, and fill date for health planpaid outpatient pharmacy services. Medical and pharmacy claims also contain cost data, including health plan-paid and patient-paid amounts.
No identifiable protected health information was accessed in the conduct of this study; therefore, institutional review board approval or waiver of approval was not required.

DEFINITION OF FIBROSING ILD PROGRESSION
Given the lack of a specific diagnosis code for progressive fibrosing ILD during the study period, disease progression was identified using claims-based proxies developed in consultation with multiple practicing pulmonologists with expertise in ILDs, as described in detail previously. 9 The proxies were chosen by these experts on the basis of their clinical experience in managing patients with ILDs and comprised procedures, therapies, tests, and other health care utilization associated with management of progressive fibrosing ILD (pulmonary function tests, oxygen titration tests, computed tomography scans, use of immunosuppressive medications or high-dose oral corticosteroids, lung transplant, oxygen therapy, palliative care, and respiratory hospitalization). Although the progression proxies have not yet been validated against medical chart data, the estimates of non-IPF progressive fibrosing ILD prevalence that were generated using these proxies in our previous report 9 were similar to those in the existing literature. 16  period) (Figure 1). Patients were eligible for inclusion if they had at least 2 non-IPF fibrosing ILD diagnoses (including codes for sarcoidosis, autoimmune ILDs, and hypersensitivity pneumonitis; described in detail previously 9 ) on different dates of service within 365 days of each other during the identification period and in the same period of continuous health plan enrollment; the date of the first fibrosing ILD diagnosis was designated as the fibrosing ILD diagnosis date. The index date was the first date with evidence of progression for patients identified with progressive disease, and the index date for notyet-progressed patients was assigned as described in the "Propensity score matching" section below. Included patients were also required to be aged at least 18 years as of the fibrosing ILD diagnosis date, to have continuous health plan enrollment with medical and pharmacy benefits for 12 months prior to the fibrosing ILD diagnosis date (baseline period) and 3 or more months after the index date (follow-up period) (Figure 1), to have an index date occurring during the same continuous enrollment period as their fibrosing ILD diagnosis date, and to have no fibrosing ILD diagnoses in the baseline period. The 3-month minimum of continuous enrollment during followup was chosen to capture a sufficient length of progression-free survival for not-yet-progressed patients and to allow sufficient observation of outcomes while minimizing the introduction of survival bias. Patients were excluded if they had claims evidence of an IPF diagnosis (ICD-10-CM J84.112) during the study period or had missing/unknown demographic information (sex, geographic region, or insurance type).

PROPENSITY SCORE MATCHING
Patients who met the study inclusion criteria were eligible for propensity  continued on next page score matching, which was used to generate study populations based on the presence or absence of progressive disease behavior (progressive and not-yet-progressed populations, respectively). The progressive cohort included patients who had evidence of progression following the fibrosing ILD diagnosis date, defined as meeting 1 or more progression proxies. The not-yet-progressed cohort included patients who had fibrosing ILD that had not yet progressed and who had 3 or more months of progression-free follow-up. These populations were not mutually exclusive; that is, patients with not-yet-progressed fibrosing ILD could serve as controls for multiple patients in the progressive cohort and were also included in the progressive cohort if they subsequently developed evidence of disease progression. Patients in the progressive population were 1:1 propensity score matched to patients in the not-yetprogressed population on the basis of baseline characteristics. Baseline variables used for matching included age category, sex, geographic region, insurance type, year of fibrosing ILD diagnosis, continuous and categorical Charlson comorbidity score, comorbidities, use of ILD medications, HCRU, and health care costs. For each patient who had fibrosing ILD that had progressed and had 3 or more months of follow-up after progression, a patient with fibrosing ILD that had not yet progressed and with the closest propensity score within a caliper of ± 0.01 was selected. The index date for not-yet-progressed patients was assigned so that the length of time from the fibrosing ILD diagnosis date to the index date was the same for the matched progressive and not-yet-progressed patients. For each matched pair, follow-up continued until the earliest of disenrollment from the health plan for either member of a

STATISTICAL ANALYSIS
Postmatch study variables were analyzed descriptively and stratified by study cohort. Numbers and percentages were provided for categorical variables; means, medians, and SDs were provided for continuous variables. To evaluate the effectiveness of the propensity score matching, postmatch differences in baseline characteristics between cohorts were assessed using standardized mean differences (SMDs); by convention, values less than 10% indicate adequate balance. 19 Differences in study outcomes between cohorts were evaluated using robust standard errors in weighted generalized linear models with clustering by individual to account for the use of some individuals multiple times in the matching. The cohort was the only predictor in this model, as patients were propensity score matched. A Poisson distribution was used for HCRU counts with the exception of inpatient stays, for which a normal distribution was used as suggested by a Park test. A γ distribution was used for health care costs.

STUDY SAMPLE
A total of 20,374 patients with ILD diagnoses were eligible for inclusion in the progressive and not-yet-progressed cohorts. The prematch populations included 11,031 patients with evidence of fibrosing ILD progression during the variable follow-up period and continuous enrollment for 3 or more months following the index date and 7,480 patients with no evidence of ILD progression during follow-up. The postmatch cohorts comprised 11,025 patients with evidence of progression matched to 11,025 patients with fibrosing ILD that had not yet progressed and 3 or more months of progressionfree follow-up ( Figure 2). The majority of patients (73.0%) were used as controls only 1 time (range: 1-10 times). Postmatch cohorts were well balanced, with SMDs less than 10% for all baseline characteristics (Table 1). In the matched progressive cohort vs the not-yet-progressed cohort, respectively, mean (SD) age was 72.7 (11.2) years vs 73.2 (11.2) years (SMD = −4.81), the percentage of women was 50.0% vs 48.3% (SMD = 3.43), and the percentage of patients with Medicare insurance was 81.8% vs 83.0% (SMD = −3.07). Comorbidity burden was substantial in both cohorts; in particular, nearly 80% of patients had hypertension (SMD = 0.92), approximately half had chronic obstructive pulmonary disease (SMD = 3.72), and more than a quarter had heart failure (SMD = 4.49). HCRU during the 12-month baseline period and associated costs were also high, with more than half of patients visiting the ED (SMD = 2.38), approximately one-third having an inpatient stay (SMD = 5.86), and mean all-cause health care costs of $34,447 and $30,969 for the progressive and notyet-progressed cohorts, respectively (SMD = 5.59). match, evidence of progression for the matched patient with fibrosing ILD, or the end of the study period. Unmatched patients were excluded from the analysis.

STUDY VARIABLES
Patient demographic characteristics (age, sex, insurance type, and geographic region) were captured as of the fibrosing ILD diagnosis date or the first claim after the fibrosing ILD diagnosis date, as available. Patient comorbidity burden, baseline medication use, baseline all-cause HCRU, and baseline all-cause health care costs were assessed during the baseline period. Study outcomes were assessed during the follow-up period and included all-cause HCRU and allcause health care costs. HCRU counts (ambulatory visits, emergency department [ED] visits, inpatient stays, and pharmacy fills) were presented as per-patient-per-month (PPPM) measures weighted by the duration of observation time to account for variable follow-up. Health care costs were calculated as total health plan plus patient-paid weighted PPPM amounts and also subdivided into medical costs (ambulatory visits, ED visits, inpatient stays, and other [eg, laboratory, home health, durable medical equipment,   (Figure 3). All medical cost subcategories were also significantly higher for the progressive cohort. The difference in medical costs between cohorts was driven primarily by higher inpatient costs for progressive vs not-yet-progressed patients ($1,729 [$7,557] vs $523 [$2,118], P < 0.001).

Discussion
In a real-world cohort of patients with newly diagnosed non-IPF chronic fibrosing ILD, adjusted all-cause health care costs and HCRU-including ambulatory visits, ED visits, inpatient stays, and pharmacy fills-were significantly higher for those with a progressive phenotype than for matched patients whose disease had not yet progressed.
Higher costs among progressive patients were driven primarily by hospitalizations; not only were weighted PPPM inpatient stays 3-fold higher in the progressive cohort than in the not-yet-progressed cohort, but among patients with at least 1 hospitalization, those with a progressive phenotype also had more inpatient days. Accordingly, weighted PPPM hospitalization costs for progressive patients were more than 3 times those for not-yet-progressed patients. Few studies have examined the economic burden of non-IPF progressive fibrosing ILD. Our results are comparable to those of , who conducted one of the only other claims-based analyses to date of HCRU and costs in a similar patient population. 15 As in our study, patients with progressive fibrosing ILD had significantly higher health care utilization and related costs than those without a progressive phenotype during the study period. 15 Mean annual medical costs per patient for progressive vs not-yet-progressed fibrosing ILD corresponded to PPPM costs of approximately $6,472 vs $5,674, respectively, 15 compared with $3,662 vs $1,627 in the present analysis. Although our conclusions are consistent with those of Olson et al, we found the magnitude of cost differences between patients with progressive vs not-yet-progressed fibrosing ILD disease behavior to be substantially higher; medical costs for the progressive cohort in the present study were more than double those of the not-yet-progressed cohort but were only 14% higher in the earlier analysis. This discrepancy may be attributable to methodological differences, as the study by Olson et al was not conducted among matched cohorts and also identified disease progression solely on the basis of pulmonologist visit frequency, leaving greater

STUDY OUTCOMES
HCRU. Follow-up all-cause HCRU for all encounter types was significantly higher for progressive patients than for not-yet-progressed patients ( Table 2). Mean weighted PPPM counts (SD) for the progressive vs not-yet-progressed cohort were 4.2 (3.6) vs 3.1 (3.3) for ambulatory visits, 0.3 (0.5) vs 0.1 (0.3) for ED visits, and 0.1 (0.2) vs 0.0 (0.1) for IP stays (P < 0.001 for all). Among patients with an inpatient stay (n = 10,899 and n = 10,842 for the progressive and not-yetprogressed cohorts, respectively), those with progressive disease also had more inpatient days than those with notyet-progressed disease (mean [

Conclusions
Among patients with incident non-IPF fibrosing ILD, all-cause HCRU and costs were significantly higher for those with a progressive phenotype than for those whose disease had not yet progressed. The cost differential was driven primarily by hospitalizations, which were longer and more frequent for progressive vs not-yet-progressed patients. Our findings complement existing data illustrating the detrimental effects of progressive fibrosing ILD on patients' lives by underscoring the substantial economic and health care burden associated with this disease behavior.
opportunity for results to be affected by possible miscategorization. Given that progressive fibrosing ILDs are hypothesized to share a common pathophysiology, it has been proposed that the burden of illness associated with this disease behavior would resemble that of IPF. 20 Indeed, our results were broadly similar to findings from previous analyses of patients with IPF, which noted substantial HCRU and monthly medical costs ranging from approximately $1,700 to $2,200 per patient (compared with $3,662 for the progressive cohort in our study). 10,12,[21][22][23] Moreover, health care costs among patients with IPF also were found to be dominated by hospitalizations, which generally were responsible for more than 50% of total medical costs. 10,12,21,22 The higher monthly medical costs observed for progressive patients in the present analysis compared with patients with IPF in earlier studies may reflect the long-standing unmet need for treatments effective in managing non-IPF progressive fibrosing ILDs.

LIMITATIONS
This study has several limitations. First, the presence of a code on a medical claim is not a confirmation of diagnosis, as codes may be entered incorrectly or included as rule-out criteria. In addition, the claims-based proxies for disease progression that were used in the absence of a specific diagnosis code for progressive fibrosing ILD have not yet been validated against medical chart data. These factors may have contributed to some degree of patient misidentification; however, it should be noted that the prevalence ranges for non-IPF progressive fibrosing ILD estimated previously using these proxies 9 were similar to those in the existing literature. 16,17 Second, the definition of progression was based on use of procedures, therapies, and tests